HRAS mutations in bladder cancer at an early age and the possible association with the Costello Syndrome

Abstract

Bladder tumours of patients <20 years have a low incidence of genetic aberrations typically found in tumours in older patients. In this study, we investigated oncogene mutations in patients with bladder cancer (BC) <20 years and compared them to older age groups. Interestingly, we observed a relatively high number of HRAS mutations in tumour from young patients. These mutations were also highly uncommon in BCs of older patients, ie, p.(Gly12Ser) and p.(Gly12Ala). Germline mutations in the HRAS gene, especially p.(Gly12Ser/Ala), cause Costello Syndrome (CS), a severe congenital disorder. Indeed, one of the patients had been diagnosed with CS. We hypothesized that some of the other patients might be mosaic for the HRAS mutation and therefore could express some of the clinical features of CS, like tumour predisposition. Hence, we isolated DNA from microdissected stroma and analysed it for HRAS mutations. In the CS patient and in patient X, the mutation was also highly expressed in normal stroma. We conclude that patient X is possibly mosaic for the HRAS mutation. These results suggest that mosaicism for oncogenic HRAS mutations may increase the risk for developing BC at a young age.

Figure 1

(a) Microdissected areas used as normal surrounding tissue in the Snapshot analysis. Microdissection ensured >90% normal stromal cells. Stroma from patient #1, 2, and 4 was derived from the same side as the bladder tumour. Stroma from patient #3 was obtained from random bladder biopsies. (b) RAS Snapshot analysis of tumour tissue and normal surrounding stroma of four patients. T, tumour tissue.